Current influenza vaccines are considered safe and effective for the general population, but post-vaccination adverse events, including autoimmune manifestiations, have been described in previously healthy individuals. Although infections, including influenza, can trigger flares in patients with autoimmune diseases, whether or not to vaccinate these patients remains a subject of discussion. In adult patients with systemic lupus erythematosus (SLE), influenza vaccine has been reported to be safe for those with quiescent disease but is not recommended for patients with active disease. Vaccination is not considered to be a causal factor for SLE initiation, but a temporal association with flare-ups has been described and the subject is still a matter of debate. Our systems biology approach to study pediatric autoimmune diseases has permitted us to discover novel pathways that can be applied to the study of humoral immune responses in healthy individuals. We now propose to use the same approach to study the response to influenza vaccination in healthy children and children with systemic autoimmunity. We propose to focus on 1) three cellular compartments that are essential for the generation and the quality of antibody responses to vaccine, i) the inducers (dendritic cells); ii) the regulators (CD4-i-, including follicular helper T cells), and iii) the effectors (B cells); 2) two diseases (SLE and JDM) where we have found alterations in these 3 compartments. The studies that we herein propose will address: 1) which are the best biomarkers of protective immune response to influenza vaccine in healthy children; 2) how unique autoimmune backgrounds set the stage for responsiveness/unresponsiveness to vaccines; 3) whether vaccination contributes to increase the breadth of autoimmunity in a disease-specific manner. Ultimately, we expect that these studies will shed light on basic aspects of humoral immune responses to vaccines and will permit us to discover biomarkers of response that can be applied to healthy children and to the general population.